Scleroderma or systemic sclerosis (SSc) is a multi-system disease with high morbidity and mortality whose etiology and pathogenesis are unknown. The pathological picture in SSc includes widespread cutaneous and visceral fibrosis, obliterative small vessel disease, and autoimmune phenomena. Increasingly, evidence is being accumulated that SSc is a complex and heterogeneous disorder in which several (or many) genes interact, perhaps also with environmental factors. In this proposal, we will use a functional genomics or systems biology approach to complement genetic association studies in identifying susceptibility/expression genes, genetic networks and molecular pathways involved in the pathogenesis of SSc. In addition to casecontrol association studies of candidate genes using SNP genotyping in several large SSc cohorts, diseaserelated gene expression profiles using DNA microarrays of SSc skin biopsies, cultured fibroblasts, and peripheral blood cells (and subsets thereof) will be determined and analyzed using novel modeling methods. In addition, selected genes in important pathways so identified will undergo gene silencing using RNA interference (RNAi) in order to determine their effects and relative merits for potential therapeutic intervention in SSc. Such a "functional genomics" approach will integrate DNA variation, gene expression, and protein function/interactions into a more comprehensive picture of molecular mechanisms, whose understanding will lead to new and more rational/targeted approaches to therapy, cure, or prevention for this devastating disease. Lay language: This study aims to better understand the genetic causes of scleroderma and determine the genetic and cellular pathways contributing to its different complicating features. Blood and skin biopsy samples from patients with scleroderma will be studied using modern genetic typing and "genomic" technologies to identify such pathways, how they cause disease, and where interference may halt the process. Such studies will increase our knowledge of the mechanisms causing scleroderma and will lead to better medical treatments, cure or prevention.